Characterization of the Renal Microvascular Effects of Angiotensin II Antagonist, DuP 753:

Abstract

The renal microvascular effects of DuP 753, an orally active imidazole angiotensin II (ANG II) receptor antagonist were assessed directly in isolated perfused hydronephrotic rat kidneys. Unilateral hydronephrosis was induced to facilitate direct visualization of renal microvessels. Hydronephrotic kidneys were perfused in vitro and microvessel diameters were measured by automated computer-assisted image processing. The administration of 0.3 nmol/L ANG II decreased afferent arteriolar (AA) and efferent arteriolar (EA) diameters by 34 +/- 3% (from 17.9 +/- 0.6 to 11.9 +/- 0.6 microns, P less than .001, n = 11) and 28 +/- 3% (from 17.1 +/- 1.3 to 12.3 +/- 1.3 microns, P less than .001, n = 11), respectively. The subsequent administration of 0.1, 1.0, and 10 mumols/L DuP 753 reversed ANG II-induced vasoconstriction of the AA by 39 +/- 10%, 81 +/- 8%, and 103 +/- 9%, and of the EA by 22 +/- 7%, 51 +/- 6%, and 87 +/- 13%, respectively. These observations indicate that DuP 753 completely blocks both the renal afferent and efferent arteriolar actions of ANG II. In light of the pathogenetic role of ANG II in mediating the deranged renal hemodynamics associated with hypertension, congestive heart failure, and some forms of renal insufficiency, our findings provide a theoretical framework for future studies assessing the potential therapeutic applicability of DuP 753 in reversing ANG II-mediated renal vasoconstriction.